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Imbalanced Expressed VDR Haplotypes in Primary Human Trabecular Bone Cells are Associated with BMD and Fractures in Men: the MrOS Study in Sweden and Hong Kong
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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URN: urn:nbn:se:uu:diva-94306OAI: oai:DiVA.org:uu-94306DiVA: diva2:168110
Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Genetic Variability in Human Bone Phenotypes: The Vitamin D Receptor Gene and the Estrogen Receptor-α Cofactor RIZ Gene
Open this publication in new window or tab >>Genetic Variability in Human Bone Phenotypes: The Vitamin D Receptor Gene and the Estrogen Receptor-α Cofactor RIZ Gene
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Important candidate genes to human bone phenotypes are those involved in the regulation of hormonal action, such as the vitamin D receptor (VDR) and the estrogen receptor-α (ERα) genes and their cofactors. RIZ1 is a specific ERα cofactor proved to strongly enhance the function of the ERα.

The main focus of this thesis has been to study genetic variants in the VDR and RIZ genes and their associations to human bone phenotypes using candidate gene and functional approaches. Specifically, polymorphisms in the VDR 3’ untranslated region (UTR) and a deletion/insertion polymorphism of a proline in the RIZ gene were investigated.

The candidate gene approach was applied to large-scale population-based cohorts of pre-and post-menopausal women from Sweden and of elderly men from Sweden and Hong Kong. VDR 3’ UTR polymorphisms were associated with peak bone mass and body composition in young women. Further analysis of common VDR 3’ UTR haplotypes confirmed the association with BMD and risk of fractures in elderly men from Sweden and Hong Kong. The VDR polymorphisms were investigated for cis-acting effects, affecting allelic expression in the normal chromosomal context of human bone cells. The VDR allelic transcripts in the bone samples were unequally expressed, suggesting presence of regulatory variants in the 3’ UTR.

The polymorphism in the RIZ gene was strongly associated to BMD in pre- and postmenopausal women and in elderly men. The functional analyses included reporter constructs containing the RIZ polymorphic variants transfected in a cell line and its abilities in coactivating the ERα were examined. The variants were functionally different in coactivating the ERα-receptor complex.

To summarize, the results of this thesis show novel evidence for functional relevant polymorphisms in candidate genes to human bone phenotypes. These polymorphisms may contribute to the variation seen in BMD and risk of fractures in the population.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 83 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 135
Medicine, Bone mineral density, candidate gene approach, polymorphism, the vitamin D receptor, the estrogen receptor α, RIZ1, cofactor, allelic imbalance, Medicin
urn:nbn:se:uu:diva-6784 (URN)91-554-6528-5 (ISBN)
Public defence
2006-05-05, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:15
Available from: 2006-04-12 Created: 2006-04-12Bibliographically approved

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